Amitriptyline for IBS-like Symptoms in Quiescent Crohn's Disease

Inclusion Criteria:

* Age 18-65 years, inclusive, at the time of consent.
* Established diagnosis of Crohn's disease, confirmed by standard clinical, endoscopic, histologic, and/or radiologic criteria.
* Quiescent Crohn's disease (qCD) defined by provider global assessment of remission for the last 3 months along with at least one of the following within the past 30 days:
* Biochemical remission defined by fecal calprotectin \< 150 mcg/g, OR
* Endoscopic remission defined by colonoscopy demonstrating Simple Endoscopic Scoring (SES)- Crohn's disease (CD) \< 4 per involved segment with no large ulcers (≥5 mm), and Rutgeerts score ≤ i1 (when applicable). OR
* Radiographic evidence of quiescent disease consistent with the protocol.
* Completion of a 12-lead electrocardiogram (ECG) within previous 12 months or at baseline demonstrating no clinically significant conduction abnormalities and a QTc ≤440 ms (males) or ≤460 ms (females).
* Presence of Irritable Bowel Syndrome-like symptoms in the setting of quiescent disease (i.e., recurrent abdominal pain or discomfort on average at least 3 days per month in the past 3 months) and bowel dysfunction (i.e. either The Bristol Stool Form Scale (BSFS) 1-2 and/or 6-7) at least 25% of the time in the past 3 months.
* At least mild-moderate abdominal pain defined by PROMIS Belly Pain score greater than or equal to 55. (PROMIS score may be re-assed once, 7 days after initial score is recorded
* Stable Irritable Bowel Disease (IBD) medical therapy for at least the past 90 days (e.g., stable biologic, small molecule inhibitors or immunomodulator therapy with no planned changes or corticosteroids at enrollment).
* Willingness to begin study medication using the amitriptyline self-titration schedule (10 mg → 50 mg as tolerated).
* If personal history of anxiety and/or depression, stable dose of psychotropic medications for at least 6 months.
* Willingness to use effective mode of contraception (e.g., OCP, IUD) for the duration of the study in women of child-bearing age.
* Ability to complete electronic questionnaires, symptom diaries, and remote assessments using the REDCap platform.
* Ability to provide written or electronic informed consent prior to participating in any study procedures.
* Stable IBD medical therapy for at least the past 90 days (e.g., stable biologic, small molecule inhibitors or immunomodulator therapy with no planned changes or corticosteroids at enrollment).

Exclusion Criteria:

Crohn's Disease-Related Exclusions

* Active Crohn's disease, based on objective markers, endoscopic activity, or radiologic inflammation.
* Hospitalization for CD flare, bowel obstruction, or other significant disease activity within the protocol-defined timeframe prior to screening.
* Actively draining perianal fistula or perianal abscess requiring antibiotics, the presence of a draining seton, intra-abdominal abscess requiring antibiotics or surgical or radiographic drainage, entero-cutaneous fistula requiring active management, or other complications suggesting active inflammation.
* Any clinically significant stricture that could explain the IBS-like symptoms
* The presence of an ileostomy or colostomy.
* The presence of a J-pouch or other stool continent pouch (e.g., Koch pouch, continent ileostomy).

Medication-Related Exclusions

* Current use of tricyclic antidepressants (TCAs).
* Current use of monoamine oxidase inhibitors (MAOIs) or other medications that have a clinically significant interaction with amitriptyline.
* Current use of Cisapride.
* History of hypersensitivity or allergy to amitriptyline or other TCAs.
* Planned change in IBD maintenance therapy during the study period.

Cardiac and Safety Exclusions

* Known cardiac conduction abnormalities, including:
* Prolonged QT interval defined as QTc \>440 ms in males or \>460 ms in females in previous 12 months or baseline ECGHistory of cardiac arrythmias, including Brugada syndrome, currently taking guanethidine or recent use of guanethidine in the past 14 days
* Recent history of myocardial infarction in the past 3 months
* Use of medications that significantly prolong QT interval (e.g., amiodarone, terfenadine, or sotalol), unless deemed safe by study medical oversight.

Psychiatric / Neurologic Exclusions

* Evidence of active major depressive disorder, defined by depression score greater than or equal to 11 on the Hospital Anxiety and Depression Scale (HADS)
* History of bipolar disorder, schizophrenia, obsessive-compulsive disorder, or other severe psychiatric conditions that may interfere with study participation
* Active or passive suicidal ideation in the last 3 months.
* Hospitalization for any psychiatric illness in the last year.
* Personal history of seizures.
* Currently taking a monoamine oxidase inhibitor (MAOI) or recent use of MAOI in the last 14 days.

Other Medical Exclusions

* Pregnancy, breastfeeding, or plans to become pregnant during the study period.
* Positive urine pregnancy test at screening, if applicable.
* History of angle-closure glaucoma.
* History of urinary retention requiring hospitalization or emergency department (ED) visit in the last 6 months.
* Current or recent substance use disorder that may interfere with participation.
* Participation in another interventional clinical trial within the exclusion window
* Inability or unwillingness to comply with study visits, medication instructions, electronic assessments, or follow-up requirements.
* Any condition that, in the investigator's opinion, would interfere with the study or pose undue risks to the participant.